Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer cases and is a leading cause of cancer-related mortality worldwide (1). Various human epidermal growth factor receptor 2 (HER2) alterations have been identified in NSCLC, including protein overexpression (2-35%), gene amplification (2-20%), and gene mutations (1-4%) (2, 3). HER2 mutations are currently a major focus of research in lung cancer, with the most common mutations occurring in exon 20, such as A775_G776insYVMA (also known as p.Y772_A775dup), which is the most frequent (4, 5). HER2-mutant NSCLC is characterized by aggressive features, including rapid progression and poor prognosis. Current therapies include platinum-based chemotherapy, HER2-targeted tyrosine kinase inhibitors (TKIs), monoclonal antibodies, and antibody-drug conjugates (ADCs) (3).

Furmonertinib is a novel third-generation epidermal growth factor receptor (EGFR)-TKI featuring a trifluoroethoxy group, which confers strong hydrophobicity, high lipophilicity, and significant electron-withdrawing properties (6). Compared to other third-generation EGFR-TKIs, furmonertinib has demonstrated good efficacy and tolerability against EGFR exon 20 insertion (ex20ins) mutant lung adenocarcinoma (7–9). However, its activity against HER2 ex20ins remains unexplored.

Here, we report for the first time a case of a patient with lung adenocarcinoma harboring a HER2 ex20ins mutation who responded to furmonertinib treatment.

The patient in this case is an elderly male who presented with lung adenocarcinoma manifesting as pneumonia, with clinical symptoms including copious sputum and significant chest tightness and shortness of breath. At the time of diagnosis, his condition was critical. As the genetic test report was pending and the patient was unable to tolerate chemotherapy, furmonertinib was initiated at 160 mg once daily, following discussion with his family. His symptoms improved, and he was discharged. The subsequent genetic test result identified an ERBB2 exon 20 mutation. He subsequently received two cycles of chemotherapy combined with immunotherapy, but the efficacy was suboptimal. Given disease progression and cost considerations, the decision was made to resume furmonertinib, which led to a positive clinical response.

For HER2-mutant NSCLC patients, the current first-line standard treatment is platinum-based chemotherapy with or without immune checkpoint inhibitors. However, the overall response rate (ORR) to platinum-based chemotherapy is approximately 43%, with a median progression-free survival (mPFS) of around 6 months (10). Nevertheless, the combination of chemotherapy and immunotherapy yields a mPFS of 8.5 months, a result that remains suboptimal (11). The poor response to chemotherapy and immunotherapy in this case aligns with previous study findings (10–12). Other treatment modalities include monoclonal antibodies, such as trastuzumab and pertuzumab, but their limited efficacy may be due to inadequate tumor penetration and insufficient blockade of downstream signaling. Tyrosine kinase inhibitors, including pan-HER TKIs (e.g., dacomitinib, neratinib, afatinib), EGFR/HER2 TKIs (e.g., lapatinib, pyrotinib, mobocertinib, BAY2927088), and selective HER2 TKIs (e.g., tucatinib, zongertinib), have yielded disappointing results in studies, with ORRs ranging from 0% to 42% and mPFS from 2.8 to 5.6 months (3). Among these, pyrotinib has shown the most promising activity, although its tolerability is limited by diarrhea, anemia, and rash. Novel therapeutic agents include anti-HER2 ADCs such as T-DXd and ado-trastuzumab emtansine (T-DM1), which have also been investigated for treating NSCLC patients with HER2 mutations. T-DXd is the first FDA-approved targeted therapy for previously treated HER2-mutant NSCLC at a dose of 5.4 mg/kg (13). While these drugs demonstrate clinical benefit, their widespread use is limited by cost and treatment-related side effects (14).

Furmonertinib is a novel, third-generation EGFR TKI with central nervous system anti-tumor activity, initially developed in China. Studies have shown that furmonertinib also elicits good responses in EGFR ex20ins mutations (7–9). Its small molecule and unique hydrophobic group form strong interactions with the L792/M793 region of the ATP-binding pocket, enabling the drug to inhibit the kinase activity of EGFR ex20ins mutations (15). Currently, there are no ongoing clinical trials investigating the efficacy and safety of furmonertinib in patients with HER2-mutant NSCLC. However, preclinical data provide a mechanistic basis for its potential activity. Studies in cell lines and murine xenograft models have demonstrated that furmonertinib and its active metabolite, AST5902, exhibit preclinical activity against HER2 exon 20 insertion mutations (e.g., V777_G778insGC[IC50 = 25nM]) and show dose-dependent antitumor efficacy (16). This preclinical evidence supports the biological plausibility of the clinical response observed in our patient. A prior case documented a response to furmonertinib in a patient with a HER2 exon 21 mutation after failure of standard therapy (17). Notably, our case is distinct in two key aspects: it involves a treatment-naïve patient and a different mutation subtype (HER2 exon 20 insertion, ERBB2 p.Y772_A775dup), representing the first report of furmonertinib’s activity in this specific frontline setting. This contrast further extends to other contexts, such as the reported activity of furmonertinib in NSCLC with co-occurring EGFR L858R and ERBB2 S310F mutations (18), which likewise differs from our case in both the specific HER2 alteration and the mutational context. Together, these observations underscore that the activity of furmonertinib may not be confined to classical EGFR mutations and may vary significantly based on the specific HER2 alteration and treatment line, highlighting the need for further genotype-directed clinical evaluation. In this case, the potential reason for this activity may lie in the shared sequence homology within the tyrosine kinase domain (TKD) between HER2 and EGFR ex20inss (Figure 4). The HER2 p.Y772_A775dup mutation reported here is the most common HER2 ex20ins mutation. Its insertion site is structurally homologous to the “near-loop” insertions in EGFR exon 20 (e.g., A767_V769dup) (19). Furmonertinib might “squeeze into” the deformed ATP-binding pocket caused by the mutation, thereby blocking tumor progression. However, the lack of covalent binding capability might explain potential suboptimal long-term efficacy and the need for higher doses of furmonertinib to achieve an effect. Rapid symptom relief (5-day) and disease control in our rechallenge scenario position furmonertinib as a viable alternative. The limitations of our case include a single-patient experience and incomplete long-term follow-up after treatment discontinuation. The patient’s decision to stop therapy due to financial constraints and decline further interventions limits our ability to assess progression-free survival or long-term tolerability. Nonetheless, the observed response supports further investigation of furmonertinib in HER2 ex20ins mutation NSCLC.

This is the first report demonstrating the clinical efficacy of furmonertinib in NSCLC harboring HER2 ex20ins mutations. Furmonertinib may serve as a viable alternative for patients intolerant to chemotherapy or limited by high costs of other treatments. Further prospective studies are needed to validate its efficacy in this setting.